Quinolineacetic acid derivatives

ABSTRACT

Compounds of the formula   WHEREIN Ar denotes an optionally substituted phenyl group or hetero-aromatic group with five or six ring members wherein the atom directly bonded to the quinoline ring is a carbon atom, R1 represents hydrogen, halogen, lower alkyl, lower alkoxy or trifluoromethyl and R2 and R3 independently of one another denote hydrogen or a lower alkyl group, esters and amides of these carboxylic acids or salts of such compounds, have antiinflammatory and analgesic activity; they are active ingredients of pharmaceutical compositions and can be used for the relief and removal of pain as well as for the treatment of rheumatic, arthritic and other inflammatory complaints; an illustrative example is Alpha -methyl-2-(2-thienyl)-6-quinolineacetic acid.

United States Patent July 29, 1975 OTHER PUBLICATIONS ChemicalAbstracts, 53:21946h, 55:223l7f Moszew. Perron et al., J. Med. Chem,Jan. 1966, Vol. 9, p. 141.

Primary Examiner-Donald G. Daus Assistant ExaminerDavid E. WheelerAttorney, Agent, or Firm.loseph G. Kolodny; Theodore O. Groeger; John J.Maitner Goschke QUINOLINEACETIC ACID DERIVATIVES ABSTRACT [75] Inventor:Richard Goschke, Bottmingen, Compounds of the formula Switzerland [73]Assignee: Ciba-Geigy Corporation, Ardsley,

N.Y. 3 221 Filed: Mar. 5, 1973 l (ZIP-COOK {[21] Appl. No.: 337,998 R[30] Foreign Application Priority Data Mar. 10, 1972 Switzerland 3549/72AI R Jan. 29, 1973 Switzerland l230/73 l [52] U.S. Cl. 260/283 S;260/247.5 G; 260/270 R;

260/283 CN; 260/283.5; 260/287 R; 260/288 R; 260/289 R; 260/29355;26O/284; 260/518 wherein Ar denotes an optionally substituted phenyl R,260518 260/286 0 424/258 group or hetero-aromatic group with five or SIXring [51] Int Cl co7d 33/48 members wherein the atom directly bonded tothe [58 Field of Search 260/287 R, 283 s qumolme a carbO atom R1represemihydwgen, halogen, lower alkyl, lower alkoxy or trlfluoro- [56]References Cited methyl and R and R independently of one another denotehydrogen or a lower alkyl group, esters and UNITED STATES PATENTS amidesof these carboxylic acids or salts of such com- 3,778,5ll 12/1973Bernasconi 260/287 R pounds h ami inflammatory and analgesic activity;

they are active ingredients of pharmaceutical compositions and can beused for the relief and removal of pain as well as for the treatment ofrheumatic, arthritic and other inflammatory complaints; an illustrativeexample is oz-methyl-2-(2-thienyl)-6- quinolineacetic acid.

16 Claims, N0 Drawings QUINOLINEACETIC ACID DERIVATIVES CH-C OOH whereinAr denotes an optionally substituted phenyl group or hetero-aromaticgroup with five or six ring members wherein the atom directly bonded tothe quinoline ring is a carbon atom, R represents hydrogen, halogen,lower alkyl, lower alkoxy or trifluoromethyl and R and R independentlyof one another denote hydrogen or a lower alkyl group, esters and amidesof these carboxylic acids or salts of such compounds, and processes fortheir manufacture.

The term lower which is used in the preceding and following text inconjunction with organic radicals, groups or compounds denotes thatorganic radicals, groups and compounds designated in this way above allcontain up to seven, preferably up to four, carbon atoms.

A lower alkyl radical is, for example, a methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec.-butyl, tert.- butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl or isoheptyl radical.

A lower alkoxy radical is, for example, a methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec.-butoxy, t.-butoxy, n-pentoxy, isopentoxy,neopentoxy, nhexoxy, isohexoxy, n-hexoxy or isohexoxy radical.

A hetero-aromatic group Ar contains, for example, in addition to thering carbon atoms one or more, preferably one, nitrogen or sulphur atomsas ring members. Particularly preferred hetero-aromatic groups arepyridyl groups, for example 2-, 3- or 4-pyridyl groups, or thienylgroups, such as 2- or 3-thienyl groups. A phenyl group orhetero-aromatic group can optionally possess one or more, preferably oneor two, identical or different substituents. Such substitutents are, forexample, lower alkyl groups, such as those mentioned above, free,etherified or esterified hydroxyl groups, such as lower alkoxy groups,for example methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy or isobutoxygroups, or halogen atoms, for example fluorine, chlorine, bromine oriodine atoms, trifluoromethyl groups, nitro groups, amino groups,preferably di-lower alkylamino groups, for example dimethylamino,N-ethyl-N-methylamino, diethylamino, di-n-propylamino,di-isopropylamino, di-n-butylamino or di-isobutylamino groups, or loweralkanoylamino groups, for example acetylamino or pivaloylamino groups.

The radical R is preferably hydrogen but can also represent lower alkyl,for example methyl or ethyl, lower alkoxy, for example methoxy orethoxy, trifluoromethyl or halogen, for example fluorine, chlorine orbromine.

Examples of esters of acids of the formula I are lower alkyl esters,wherein lower alkyl has the abovementioned meaning.

Amides of acids of "=e formula I are optionally substituted amides, suchmonoor di-lower alkylamides, wherein lower alkyl has the abovementionedmeaning, and also hydroxamic acids.

By salts of the compounds of the formula I and their functionalderivatives there are above all understood salts of the acid compoundswhich fall under the definition, such as the free carboxylic acids, andalso the corresponding hydroxamic acids with bases, as well as acidaddition salts.

Salts of the acids which fall under the present invention are, forexample, alkali metal salts, alkaline earth metal salts or earth metalsalts, such as sodium salts, potassium salts, lithium salts, magnesiumsalts, calcium salts or aluminium salts, and also ammonium salts, forexample with ammonia, with lower alkylamines which are optionallysubstituted, for example by hydroxyl or phenyl, such as with ethylamine,Z-aminoethanol, benzylamine, diethanolamine, 2-dimethylaminoethanol,trimethylamine or triethylamine, with lower alkylenediamines, such asethylenediamine, with procaine and with cyclic lower alkyleneamines,wherein a carbon atom can optionally be replaced by a heteroatom, suchas oxygen, such as pyrrolidine, piperidine and morpholine.

Acid addition salts, such as pharmaceutically usable non-toxic acidaddition salts, are, for example, salts with inorganic acids, such ashydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,nitric acid or perchloric acid, or with organic acids, especiallyorganic carboxylic acids or sulphonic acids, such as loweralkanemonocarboxylic or lower alkanedicarboxylic or loweralkenemonocarboxylic or lower alkenedicarboxylic acids which areoptionally substituted, for example by hydroxyl, 0x0 or phenyl, forexample formic acid, acetic acid, propionic acid, succinic acid,glycollic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid orphenylacetic acid, benzoic acids which are optionally substituted, forexample by amino or hydroxyl, for example benzoic acid, 4-aminobenzoicacid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid andaminosalicylic acid, and also embonic or nicotinic acid, as well asoptionally substituted lower alkanesulphonic acids or loweralkenesulphonic acids, such as methanesulphonic acid, ethanesulphonicacid, hydroxyethanesulphonic acid and ethylenesulphonic acid, orbenzenesulphonic acids which are optionally substituted, for example byhalogen or lower alkyl, such as benzenesulphonic acid,halogenobenzenesulphonic acid and toluenesulphonic acid.

The compounds according to the invention possess valuablepharmacological properties, especially an antiinflammatory and analgesicactivity, as well asa favourable therapeutic index. Theanti-inflammatory activity manifests itself, for example, in rats in thekaolin paw oedema test, according to L. Riesterer and R. Jaques, Helv.physiol. pharmakol. Acta 25 156 (1967), in which the compounds accordingto the invention possess a detectable action on peroral administrationof about 10 to mg/kg.

The analgesic effects can be demonstrated, for example, with the aid ofthe writhing test in mice, such as according to the method developed bySiegmund et al., Proc.Soc.Exptl. Biol.Med., volume 95, page 729 (1957),at oral doses of about 10 to about I mg/kg.

The compounds of the present invention can therefore be used asanalgesic, especially as antiinflammatory, agents, above all for thetreatment of arthritic symptoms. They can also be used as intermediateproducts in the manufacture of other pharmacologically active, valuablecompounds.

Preferred compounds of the present invention are those of the formula Iin which Ar denotes a phenyl group which is optionally substituted bylower alkyl or lower alkoxy with at most 4 carbon atoms, fluorine,chlorine, bromine or trifluoromethyl, a thienyl group or pyridyl group,R, denotes hydrogen or chlorine, R and R independently of one anotherdenote hydrogen or lower alkyl with at most 4 carbon atoms, and one ofthe groups Cl-I(R )COOl-I and R occupies the 6- position and the otherthe 8-position and the group R occupies the 4-position, their loweralkyl esters with at most four carbon atoms, unsubstituted andN-hydroxysubstituted amides thereof, and salts of these compounds.

Particularly preferred compounds of the formula I are those wherein Ardenotes a phenyl group which is optionally substituted by fluorine,chlorine, methyl, methoxy or trifluoromethyl, or a thienyl group, Rdenotes hydrogen, R denotes hydrogen or methyl in the 4-position and Rdenotes hydrogen or methyl and wherein the CI-I(R )COOI-I group occupiesthe 6- position, methyl esters of these acids and their salts withbases.

The compounds of the present invention are obtained according to methodswhich are in themselves known. Thus they can be formed, for example, ifin a compound of the formula Ar 1 (II) wherein X represents a radicalwhich can be converted into an optionally esterified or amidised groupof the formula -CI-I(R )C(=O)-OI-I (Ila), X is converted into anoptionally esterified or amidised group of the formula -CH(R )C(=O)-OH(Ila) and, if desired, a resulting compound is converted into anothercompound within the framework which has been defined.

Thus it is possible, in a compound of the formula II, wherein Xrepresents a radical of the formula -CH(R- )X (Ilb), wherein X,represents a radical which can be converted into the optionallyesterified or amidised carboxyl group, to convert X, into an optionallyesterified or amidised carboxyl group. A group X, is, for example, anitrile group, an optionally substituted thiocarbamoyl group, anetherified hydroxyl or mercaptoformimidoyl group or a trihalogenomethylor trilower alkoxymethyl group.

An optionally substituted thiocarbamoyl group is, for example, a N-loweralkylthiocarbamoyl or N,N-dilower alkylthiocarbamoyl group, and also alower alkyleneamino-thiocarbonyl group, wherein the carbon atoms of thelower alkylene radical can preferably be interrupted by a nitrogen or asulphur atom, but especially an oxygen atom, such as, for example, amorpholinothiocarbonyl group. An etherified hydroxyformimidoyl group(that is to say a O-etherified group of the formula HOC(=NH)) is inparticular lower alkoxyformimidoyl, for example methoxyformimidoyl orethoxy-formimidoyl, whilst an etherified mercaptoformimidoyl group (thatis to say a S-etherified group of the formula l-lS-C(=Nl-I)) inparticular represents lower alkylthioformimidoyl, for examplemethylthio-formimidoyl or ethylthioformimidoyl. A trihalogenomethylgroup is, for example, trichloromethyl and a tri-lower alkoxymethylgroup is, for example, trimethoxymethyl or triethoxymethyl.

The conversion of a group X, into an optionally esterified or amidisedcarboxyl group can be effected by hydrolysis.

The hydrolysis is advantageously carried out in a basic or acid medium.Bases are, for example, inorganic bases, such as alkali metal hydroxidesor alkaline earth metal hydroxides, for example sodium hydroxide orcalcium hydroxide, and also salts of these hydroxides with weak acids,such as carbonic acid, for example the corresponding carbonates andbicarbonates. It is also possible to use organic bases, preferablystrong organic bases, such as quaternary ammonium hydroxides, forexample quaternary lower alkylammonium hydroxides, such astetramethylammonium hydroxide and tetra-nbutylammonium hydroxide, aswell as their salts with weak acids, such as carbonic acid, for examplethe corresponding carbonates and bicarbonates, and also tertiary amines,such as tert.-lower alkylamines, for example trimethylamine,diisopropylethylamine, dicycloalkyl-lower alkylamines, such asdicyclohexylethylamine, nitrogen-containing heterocyclics, such asN-lower alkylpiperidines and alkylmorpholines, for example N-methylpiperidine or N-methylmorpholine, and also basic ion exchangers.

The basic hydrolysis is carried out in water, advantageously in amixture of water and a solvent which is inert under the reactionconditions and is miscible with water. Such solvents are, for example,water-miscible ether-like liquids, such as dioxane, ethylene glycollower alkyl ethers, such as ethylene glycol monomethyl ether or dimethylether, ethylene glycol monoethyl ether or diethyl ether, diethyleneglycol lower alkyl ethers, such as diethylene glycol monomethyl ether ordimethyl ether, and diethylene glycol monoethyl ether or diethyl ether,liquid alcohols, such as lower alkanols, for example methanol or ethanolor sulphoxides, such as di-lower alkylsulphoxides or loweralkylenesulphoxides, for example dimethylsulphoxide.

The reaction is preferably carried out at elevated temperature, forexample between about 20C and C, if appropriate in a closed vessel.

The acid hydrolysis is advantageously carried out in the presence ofstrong acids. Strong acids are, for example, mineral acids, for examplehydrogen halide acids, such as hydrochloric acid and hydrobromic acid,inorganic oxygen acids, such as sulphuric acid, phosphoric acid orperchloric acid, strong organic acids, for example aliphatic or aromaticsulphonic acids such as optionally halogen-substituted loweralkanesulphonic acids, for example methanesulphonic acid ortrifluoromethanesulphonic or trichloromethanesulphonic acid, orbenzenesulphonic acids which are optionally substituted, for example byalkyl, such as methyl, phenyl, nitro or halogen, such as chlorine orbromine, for example benzenesulphonic acid, p-toluenesulphonic acid,p-diphenylsulphonic acid, p-nitrobenzenesulphonic acid orp-bromobenzenesulphonic acid. In the acid hydrolysis, solvents used arewater or a mixture of water and a solvent which is inert under thereaction conditions and is water-miscible. Such solvents are above alllower alkanecarboxylic acids, such as acetic acid, and also theabovementioned water-miscible ether-like liquids.

According to a preferred method of carrying out the reaction, a compoundof the formula II, wherein X corresponds to the formula llb and Xrepresents, for example, the nitrile group or a trichloromethyl group,is first treated with a liquid acid which comes under the abovementionedacids, for example with sulphuric acid, in the presence or absence of adiluent, for example of a lower alkanecarboxylic acid, such as aceticacid, and the resulting mixture is decomposed with water.

Th reaction is advantageously carried out at normal or elevatedtemperature, preferably between about and 120C.

The hydrolysis of the nitriles and thioamides to the correspondingcarboxylic acids takes place via the corresponding amides asintermediate stages; these amides can be isolated if desired. Thehydrolysis of the imidoesters and orthoesters to the acids takes placevia the corresponding esters as intermediate stages which can also, ifdesired, be isolated.

The compounds of the formula I, as well as their esters or amides, andalso salts of such compounds, can also be manufactured if a compound ofthe formula I], wherein X represents a group of the formula Cl-l(R- )-X(He), in which X denotes a metallic radical, is treated with afunctional derivative of carbonic acid.

A metallic radical is, for example, an alkali metal atom or asubstituted alkaline earth metal atom, zinc atom or cadmium atom, suchas a halogenomagnesium group as well as a lower alkyl-zinc or loweralkylcadmium group, for example a methylor ethyl-zinc group or -cadmiumgroup, but preferably the lithium atom or a chloromagnesium,bromomagnesium or iodomagnesium group.

Functional derivatives of carbonic acid are preferably its esters, forexample lower alkyl esters thereof, such as diethyl carbonate, alsohalides, such as phosgene, carbamoyl halides, such as diethylcarbamoylchloride, and especially the anhydride of carbonic acid, that is to saycarbon dioxide. The reaction is advantageously carried out in a solvent,such as an inert organic solvent, for example an aliphatic or aromatichydrocarbon, such as pentane, benzene or toluene, and also inhydrocarbon mixtures, such as petroleum ether or ligroin, but preferablyin one of the abovementioned ether-like solvents. The reaction iscarried out at lowered or elevated temperature, for example betweenabove 80 and about +100C, preferably between 0 and 40C.

According to a further process variant, compounds of the presentinvention can be manufactured by treating a compound of the formula II,wherein X is a group of the formula -Cl-l(R )X (Ild), wherein Xrepresents an optionally etherified hydroxyl group, with carbon monoxideor with formic acid or with a reactive functional derivative thereof.

An etherified hydroxyl group X is, for example, a lower alkoxy group,such as the methoxy group.

Reactive functional derivatives of formic acid are above all theiresters, such as lower alkyl esters, for example formic acid methyl esteror formic acid ethyl ester and orthoformic acid methyl ester and ethylester. The reaction can, for example, be carried out at high pressuresand/or temperatures, for example at up to about 400 atmospheres andabout 300C, preferably in the presence of a heavy metal catalyst, suchas a nickel salt or cobalt salt, or of a carbonyl derivative thereof,without solvents or in water. In another process variant, the carbonmonoxide, which can, if desired, be evolved from suitable reagents, suchas formic acid in the presence of high-boiling mineral acids, such assulphuric acid or phosphoric acid, can be used in the presence of theseacids at lowered or elevated temperature, for example between about -10and 200C.

According to a further process variant, the compounds of the presentinvention can be manufactured by oxidising a compound of the formula II,wherein X represents a group of the formula CH(R )CHO (lle).

The oxidation can be carried out with the aid of standard oxidationmethods, for example by treatment with oxygen (either in the pure formor in the form of air), preferably in the presence of a suitablecatalyst, such as a silver catalyst, manganese catalyst, iron catalystor cobalt catalyst, or with oxidising agents such as hydrogen peroxide,or a nitrogen oxide (nitric oxide), oxidising acids or salts thereof,such as hypohalous acids, periodic acid, nitric acid or percarboxylicacids or corresponding salts, such as alkali metal salts thereof, for example sodium hypochlorite or sodium periodate, peracetic acid,perbenzoic acid or monoperphthalic acid, heavy metal salts or oxides,such as alkali metal chromates, for example sodium chromate or potassiumchromate, or alkali metal permanganates, for example sodium permanganateor potassium permanganate, chromium-Ill or copper-ll salts, for examplehalides or sulphates, or silver, mercury, vanadium-V, chromium- Vl ormanganese-IV oxides, in an acid or alkaline me-. dium. Additionally, theoxidation can be carried out electrochemically.

The oxidation is advantageously carried out in solvents which are stabletowards the oxidising agents used, for example water or ketones, such aslower alkyl ketones, for example acetone or methyl ethyl ketone, loweralkanecarboxylic acids, such as acetic acid, hydrocarbons such asbenzene, chlorinated hydrocarbons, such as chlorobenzene, carbontetrachloride or tetrachloroethane and also nitrogen-containingheterocyclic compounds, such as pyridine. The reaction is carried out atlowered, normal or elevated temperature, for example between about -10and about C.

Aldehyde starting substances can be formed in situ, for example bystarting from compounds which can be oxidised to the former, for examplefrom appropriate halogenomethyl compounds of the formula II, wherein Xrepresents a radical of the formula Cl-l(R )-X (llf), in which X,denotes, for example, halogenomethyl, and employing these in theoxidation reaction. In that case, the above aldehyde starting substancesare obtained as intermediate products.

Compounds of the present invention can furthermore be obtained if in acompound of the formula II, wherein X denotes an optionally esterifiedor amidised group of the formula -C(=R )C(=O)OH (Hg), in which Rrepresents a lower alkylidene group, R; is reduced to a lower alkylgroup.

The above reduction is carried out, for example, by treatment with ametal, for example with an alkali metal, such as sodium, in the presenceof a proton donor, preferably a lower alkanol, such as ethanol but ispreferably carried out with catalytically activated hydrogen, using asthe catalyst a transition metal or transition metal derivative, such asnickel, platinum, platinum oxide or palladium, if desired on a neutralcarrier, such as kieselguhr, calcium carbonate or animal charcoal. Thehydrogenation is advantageously carried out in the presence of asolvent, for example water or an inert organic solvent, for example oneof the abovementioned etherlike solvents, an alcohol, such as a loweralkanol, for example ethanol, an organic acid, such as a loweralkanecarboxylic acid, for example acetic acid, or an ester of such anacid, for example with lower alkanols, such as ethyl acetate, or aliquid amide, such as a di-lower alkylamide of a lower alkanecarboxylicacid, for example dimethylformamide or dimethylacetamide and, ifdesired, at elevated pressure, for example up to 50 atmospheres gauge,and/or whilst cooling or warming, for example between about and 100C.

According to a further process variant, the com pounds of the presentinvention can be manufactured by decarboxylating a compound of theformula ll, wherein X denotes an optionally esterified or amidised groupof the formula -C(R )(X )-C(=O)OH (Ilh), in which X denotes .a carboxylgroup.

To carry out the decarboxylation a starting material is warmed in thepresence or absence of a solvent and- /or of a catalyst.

Solvents used are, in addition to water, organic solvents, preferablythose of higher boiling point, such as alcohols, for example loweralkanols, such as ethanol, polyhydric alcohols, such as loweralkanediols or alkanetriols, for example glycerine or glycol, ether-likesolvents, such as di-lower alkyl ethers, for example dibutyl ether,ethylene glycol monoor di-lower alkyl ethers or diethylene-glycol monoordi-lower alkyl ethers, such as ethylene glycol monomethyl ether,ethylene glycol dimethyl ether, diethylene glycol monomethyl ether ordiethylene glycol dimethyl ether, or diaryl ethers, for example diphenylether, liquid nitrogen bases, such as lower alkylamines, for exampletriethylamine and ethyldiisopropylamine, dicycloalkyl-lower alkylamines,such as dicyclohexyl-methylamine, aryllower alkylamines, for exampledimethylaniline, optionally substituted nitrogen-containing heterocycliccompounds, for example pyridine, picolines or collidines, and alsoquinoline, and liquid amides, such as dilower alkylamides of loweralkanecarboxylic acids, for example dimethylformamide ordimethylacetamide. Copper of copper salts, such as copper-l chloride,can, for example, serve as catalysts. The reaction is carried out atelevated temperature, for example between about 50 and 250C.

The compounds of the present invention can also be manufactured if acompound of the formula 11, wherein X denotes a group of the formulaCH(R )X (lli), in which X represents an optionally esterifiedcarboxycarbonyl group, is decarbonylated. The decarbonylation can, forexample like the above decarboxylation, be carried out at elevationtemperature and preferably in the presence of a solvent.

According to a further process variant, the compounds of the presentformula can also be manufactured if a compound of the formula II,wherein X represents a group of the formula C(=O)--C(N )--R (Ilk), isreacted with water, an alcohol, ammonia or an amine.

The above reaction is carried out in accordance with an Arndt-Eisten andWolff method, preferably in the presence of a noble metal or of a noblemetal salt as the catalyst, for example of copper or platinum orpreferably of a silver salt, such as silver nitrate or silver oxide, orof a complex metal salt thereof with sodium thiosulphate. The reactionis preferably carried out in the presence of a solvent, advantageouslyin an excess of of the water, alcohol or amine required for thesolvolysis, or of an inert diluent, such as an ether-like solvent, forexample dioxane, a ketone, such as a lower alkylketone, for exampleacetone, a carboxylic acid, such as a lower alkanecarboxylic acid, forexample acetic acid, or an amide, such as a di-lower alkylamide of alower alkanecarboxylic acid, for example dimethylformamide ordimethylacetamide. The reaction is preferably carried out at normal orelevated temperature, for example between about 20 and C.

According to a particularly advantageous embodiment, a solution of thediazoketone used as the starting material is slowly added to an aqueoussolution of silver nitrate and sodium thiosulphate or to a suspension ofsilver oxide in an aqueous solution of sodium sulphate, with thetemperature of the aqueous solution or suspension being about 6070C. Itis furthermore possible to treat a solution of the diazoketone in analcohol, for example in a lower alkanol, at its boiling point, withfreshly prepared silver oxide added in portions until no furthernitrogen evolution is detectable.

The compounds of the present application can also be obtained if ananiline derivative of the formula cu -coon 1 l (III) or an ester or anamide thereof with regard to the carboxyl group is condensed with acompound of the formula ArZ (IV) in which Z and Z denote radicals whichtogether with the aniline radical are capable of forming the desiredquinoline ring and, if desired, a resulting compound is converted intoanother compound of the invention within the defined scope.

Thus, a compound of the formula III, wherein Z, denotes a hydrogen atom,can be condensed with a compound of the formula IV, wherein Z representsa radical of the formula Cl-l=C(R )-C(R ")=O (lVa), in which one of thegroups R and R denoted hydrogen and the other corresponds to thedefinition of R under the formula I, in accordance with the method ofDoebner and Miller. The condensation is advantageously carried out inthe presence of acids, such as of mineral acids, for example hydrogenhalide acids, such as hydrochloric acid, oxygen acids, such asphosphoric acid or sulphuric acid, strong organic acids, such asoptionally substituted lower alkylsulphonic acids of benzenesulphonicacids, such as toluenesulphonic acid or trifluoromethanesulphonic acid,or of Lewis acids, such as, for example, halides, for example of zinc,and also of boron, aluminium, titanium, tin, phosphorus, antimony andiron, such as zinc chloride, boron trifluoride, aluminium chloride,titanium tetrachloride, tin tetrachloride, phosphorus pentachloride orantimony pentachloride or iron trichloride. The reaction isadvantageously carried out in the presence of an oxidising agent, suchas an organic nitro compound, for example an optionally substitutednitrobenzene, such as nitrobenzene or o-nitrobenzoic acid, of atransition metal salt of high oxidation level, for example a ferricsalt, such as ferric chloride, of an oxidising acid, such as arsenicacid, or of a halogen, such as iodine. The reaction is preferablycarried out in the absence of a diluent or in a liquid condensationagent as the solvent, and at elevated temperature, for example betweenabout 50 and 250C.

According to another process variant, compounds of the present inventioncan be obtained if a compound of the formula III, wherein Z, denotes agroup of the formula -COR (IIIb), is condensed with a compound of theformula IV, wherein Z is a group of the formula COCH R (IVb), in whichone of the groups R and R denotes hydrogen and the other corresponds tothe definition of R under the formula I, in accordance with Friedlandersmethod. The condensation agents used are the acid agents listed underthe Doebner-Miller condensation, advantageously in the absence of adiluent or in an excess of the liquid condensation agent as solvent.Preferably, the reaction is carried out at elevated temperature, forexample between about 50 and 250. I

According to a further process variant, compounds of the presentinvention can be obtained if a compound of the formula III, wherein Zdenotes a group of the formula -CH R (Illc), are condensed with acompound of the formula IV, wherein Z denotes the radical of the formulaC(=O)-C(R ")=O (IVc), in which one of the groups R and R denoteshydrogen and the other corresponds to the definition of R under theformula I, according to Kulischs method. The condensation can be carriedout in the presence of the acid agents listed under the Doebner-Millercondensation, but advantageously strong bases are used as catalysts, forexample the strong bases listed earlier, for example alkali metalhydroxides or alkali metal alcoholates such as alkali metal loweralkanolates, for example potassium hydroxide or potassium ethanolate.The acid condensation is advantageously carried out without solvents orin a liquid condensation agent as the solvent whilst the base-catalysedcondensation is preferably carried out in a solvent, for example inwater, or in organic solvents, such as lower alkanols, for exampleethanol, and also in ether-like solvents, such as ethylene glycol loweralkyl ethers, for example ethylene glycol monomethyl ether, preferablyat an elevated temperature, for example between about 50 and 250.

Resulting compounds can be converted into one another in a manner whichis in itself known. Thus, for example, resulting free acids can beesterified using alcohols, in the presence of esterifying agents, suchas strong acids, for example hydrogen halide acids such as hydrochloricacid, oxygen acids, such as sulphuric acid, optionally substitutedbenzenesulphonic acids such as benzenesulphonic acid orp-toluenesulphonic acid, or agents which split off water, such asdi-lower alkylor dicycloalkylcarbodiimides, such asdicyclohexylcarbodiimide, or using diazo compounds such as diazo-loweralkanes, for example diazomethane, or can be converted into acid halidesby treatment with suitable halogenating agents, such as thionyl halides,for

example thionyl chloride, or phosphorus halides or oxyhalides, forexample phosphorus chloride or oxychloride.

Resulting esters can be hydrolysed to free acids, for example bytreatment with suitable basic agents, such as aqueous alkali metalhydroxides, or can be transesterified into other esters by means ofalcohols in the presence of acid or alkaline agents, such as mineralacids or complex heavy metal acids, as well as alkali metal carbonatesor alkali metal alcoholates. Esters can be converted into amides bytreatment with ammonia or appropriate amines.

Resulting acid halides can be converted by treatment with alcohols, aswell as ammonia or amines, and resulting metal salts or ammonium saltscan be converted by treatment with alcohols or appropriate halides, forexample chlorides or bromides, or with thionyl halides, for examplethionyl chloride, phosphorus pentoxide, phosphorus halides, for examplephosphorus pentachloride, or phosphorus oxyhalides, for examplephosphorus oxychloride, into esters, halides or amides, depending on thechoice of the starting substances and the use of reagents.

Resulting amides can be hydrolysed under acid or alkaline conditions,for example by treatment with aqueous mineral acids and/or carboxylicacids or alkali metal hydroxides, and can also be alcoholised ortransaminated.

Resulting salts or esters in which R represents hydrogen, can bealkylated, in the a-position to the functionally modified carboxylgroup, by means of a reactive ester of a lower alkanol. Reactive estersof lower alkanols are, for example, those with strong acids, such ashydrogen halide acids, such as hydriodic acid or hydrobromic acid,oxygen acids, such as sulphuric acid, or strong organic, for examplealiphatic or aromatic, sulphonic acids, such as optionallyhalogen-substituted lower alkanesulphonic acids, for examplemethanesulphonic acid or trifluoromethanesulphonic ortrichloromethanesulphonic acid, or with benzenesulphonic acids which areoptionally substituted, for example by lower alkyl, for example methyl,phenyl, nitro or halogen, for example chloride or bromine, for examplebenzenesulphonic acid, p-toluenesulphonic acid, p-biphenylsulphonicacid, p-nitrobenzenesulphonic acid or p-bromobenzenesulphonic acid.

The alkylation is advantageously carried out in the presence of a base,such as of an alcoholate, for example an alkali metal lower alkanolate,for example so dium ethylate or potassium tert.-butylate, anv alkalimetal amide or alkali metal hydride, such as sodium amide or sodiumhydride, an alkali metal amide derived from a secondary amine, forexample an alkali metal di-lower alkylamide, such as lithiumdiisopropylamide, or an organic alkali metal compound, for exampletriphenylmethyl-sodium, and also a strong organic nitrogen-containingbase, such as a tetra-lower alkylammonium lower alkanolate, such astetra-nbutylammonium methylate.

The reaction is advantageously carried out in the presence of an organicsolvent, in the case of lower alkanolates preferably in thecorresponding lower alkanols, and in the case of the other bases whichhave been mentioned, for example, in ether-like liquids, such as indi-lower alkyl ethers, for example diethyl ether, in ethylene glycoldi-lower alkyl ethers, such as ethylene glycol dimethyl ether, cyclicethers, such as tetrahydrofurane or dioxane, hydrocarbons, such asbenzene or to]- uene, di-lower alkylamides of lower alkanoic acids, suchas dimethylformamide or dimethylacetamide, and sulphoxides, for exampledi-lower alkylsulphoxides, such as dimethylsulphoxide. The directalkylation is advantageously carried out at temperatures between and120C.

Resulting compounds can be halogenated in the aromatic radical Ar, forexample using halogen, preferably in the presence of a Lewis acid, forexample an iron-Ill halide, aluminium halide, antimony-III halide ortin-IV halide, or using a halogenating agent, for example hydrochloricacid in the presence of hydrogen peroxide, or of an alkali metalchlorate, for example sodium chlorate, a nitrosyl halide, for examplenitrosyl chloride or nitrosyl bromide, or a halogeno-, for examplebromosuccinimide or -phthalimide.

It is furthermore possible to introduce a nitro group into the aromaticradical Ar, for example by treatment with nitric acid or with nitratesalts under acid conditions, for example in the presence of sulphuricacid or trifluoroacetic acid. In a resulting nitro compound, the nitrogroup can be reduced to the amino group, for example by treatment withcatalytically activated hydrogen or with chemical reducing agents(nascent hydrogen).

Resulting compounds with a primary amino group can be reacted withreactive esters of alcohols or glycols, and with reactive functionalderivatives, such as halides, for example chlorides, or anhydrides ofacids, and can thus be converted into compounds with secondary ortertiary amino groups with quaternary ammonium groups, and into acylatedamino groups. When treated with nitrous acid, resulting compounds with afree amino group yield diazonium salts, which can be converted into thecorresponding hydroxy, halogen or lower alkoxy compounds by theSandmeyer reaction, for example by hydrolysis at elevated temperatures,treatment with copper-II halides or with a lower alkanol, preferablyunder neutral or slightly acid or alkaline conditions.

In resulting phenolic products, phenolic hydroxyl groups can beetherified, for example using the corresponding metal phenolates oralkali metal phenolates, by treatment with reactive esters of loweralkanols, such as lower alkyl halides, lower alkyl sulphates or loweralkyl sulphonates, as well as by using diazo compounds, such asdiazo-lower alkanes. Resulting phenol ethers can be split, for exampleby treatment with strong acids or acid salts, such as hydrobromic acidand acetic acid, as well as pyridine hydrochloride.

A resulting free acid can be converted into a salt in a manner which isin itself known, for example by reaction with an approximatelystoichiometric amount of a suitable salt-forming agent, such as ammonia,an amine or an alkali metal or alkaline earth metal hydroxide,

carbonate or bicarbonate. Ammonium salts or metal salts obtainable inthis way can be converted into the free acid by treatment with an acid,for example hydrochloric acid, sulphuric acid or acetic acid, until therequisite pH value is reached.

A basic compound obtained can be converted into an acid addition salt,for example by reaction with an inor' ganic or organic acid or anappropriate anion exchanger and isolation of the salt formed. Aresulting acid addition salt can be converted into the free compound bytreatment with a base, for example an alkali metal hydroxide, ammonia ora hydroxyl ion exchanger.

The salts can also be used for the purification and identification ofthe free compounds; thus, free compounds can be converted into theirsalts, these can be isolated from the crude mixture, and the freecompounds can then be obtained from the isolated salts. In view of theclose relationships between the new compounds in the free from and inthe form of their salts the free compounds or the salts are to beunderstood, in the preceding and following text, where appropriate toinclude the corresponding salts or free compounds, in general sense andintended use.

Resulting isomer mixtures can be separated into the individual isomersin a manner which is in itself known, for example by fractionaldistillation or crystallisation and/or by chromatography. inert productscan be separated into the optical antipodes, for example by separation,presence as fractional crystallisation, of mixtures of diastereoisomericsalts, for inert with dor l-tartaric acid, or with d-a-phenylethylamine,d-a-( l-naphthyl)- ethylamine or l-cinchonidine and, if desired,liberation of the free antipodes from the salts.

The above reactions are carried out in accordance with methods which arein themselves known, for example in the absence or presence of diluents,preferably those which are insert towards reactants and are capable ofdissolving them, if necessary in the presnce of catalysts, condensationagents or neutralising agent, in an insert gas atmosphere, for example anitrogen atmosphere, whilst cooling or warming and/or under elevatedpressure.

The invention also relates to those modifications of the above processaccording to which a compound formed has an intermediate product at anystage is used as the starting material and the remaining stage or stagesis or are carried out therewith, or the process is interrupted at anystage, or according to which starting substances are formed under thereaction conditions or are used in the form of salts or reactivederivatives.

The new compounds of the present invention can be administeredperorally, rectally or pareiiterally. Suitable unit dosage forms, suchas dragees, tablets, suppositories or ampoules, preferably contain, asthe active substance, 10-500 mg of a compound of the formula I or of asalt of a free acid falling under this formula with a pharmaceuticallytolerated inorganic or organic base. In unit dosage forms for peroraluse, the content of active substance is preferably between 10% and Tomanufacture such unit dosage forms, the active substance is combined,for example, with solid, pulverulent excipients, such as lactose,sucrose, sorbito] or mannitol; starches, such as potato starch, cornstarch or amylopectin, and also laminaria powder or citrus pulp powder;cellulose derivatives or gelatine, optionally with the addition oflubricants, such as magnesium stearate or calcium stearate orpolyethylene glycols, to give tablets or to give dragee cores. Thelatter are coated, for example, with concentrated sugar solutions whichcan, for example, additionally contain gum arabic, talc and/or titaniumdioxide, or with a lacquer dissolved in easily volatile organic solventsor solvent mixtures. Dyestuffs can be added to these coatings, forexample to characterise various doses of active compounds. Furthersuitable oral unit dosage forms are push-fit capsules of gelatine aswell as soft, sealed capsules of gelatine and a plasticiser, such asglycerine. The former preferably contain the active compound as granulesmixed with lubricants, such as talc or magnesium stearate, andoptionally with stabilisers, such as sodium metabisulphite (Na S O orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids, such as liquid polyethyleneglycols, and again stabilisers can be added. Possible unit dosage formsfor rectal use are, for example, suppositories which consist of acombination of an active compound with a suppository base compositionbased on natural or synthetic triglycerides (for example cacao butter),polyethylene glycols or suitable higher fatty alcohols, and gelatinerectal capsules which contain a combination of the active compound withpolyethylene glycols.

Ampoule solutions for parenteral, especially intramuscular orintravenous, administration contain, for example, a compound of thegeneral formula I in a concentration of, preferably, O.55%, as anaqueous dispersion prepared with the aid of customary solubilisingagents and/or emulsifiers and, optionally, stabilisers, or an aqueoussolution of a pharmaceutically tolerated water-soluble salt of a freeacid falling under the general formula 1.

Further possible forms for parenteral administration are lotions,tinctures and ointments for percutaneous administration, prepared withthe usual auxiliaries.

The instructions which follow are intended to explain in more detail themanufacture of tablets and drages:

a. 1,000 g of active substance, for example Z-phenyl- 6-quinolineaceticacid are mixed with 550 g of lactose and 292 g of potato starch and themixture is moistened with an alcoholic solution of 8 g of gelatine andgranulated through a sieve. After drying, 60 g of potato starch, 60 g oftalc and 10 g of magnesium stearate and c8 g of highly disperse silicaare mixed in and the mixture is pressed to give 10,000 tablets eachweighing 200 mg and each containing 100 mg of active substance, thetablets being provided with breaking grooves, if desired, for moreaccurate selection of the dosage.

b. 200 g of active substance, for example a-methyl-Z-[p-chlorophenyl)-6-quinolineacetic acid, are well mixed with 16 g ofcorn starch and 6 g of highly disperse silicon dioxide. The mixture ismoistened with a solution of 2 g of stearic acid, 6 g of ethyl celluloseand 6 g of stearin in approx. 70 ml of isopropyl alcohol and isgranulated through a III sieve (Ph. Helv.V). The granules are dried forapprox. 14 hours and then beaten through a Illa sieve. Thereafter theyare mixed with 16 g of talc and 18 g of magnesium stearate and pressedto give 1,000 drage cores. These are coated with a concentrated syrup of2 g of shellac, 7.5 g of gum arabic, 0.15 g of dyestuff, 2 g of highlydisperse silicon dioxide, g of talc and 53.35 g of sugar and are dried.

The resulting drages each weigh 360 mg and each contain 200 mg of activesubstance.

0. 50.0 g of a-methyl-2-phenyl-6-quinolineacetic acid are dissolved in amixture of ml of l N sodium hydroxide solution and 500 ml of boiledpyrogenfree water and the solution is made up to 2,000 ml with the sametype of water. The solution is filled into 1,000 ampoules each holding 2ml, and is sterilised. One ampoule holding 2 ml contains 50 mg of activesubstance in the form of the sodium salt.

d. 50 g of a-methyl-2-(p-chlorophenyl)-6- quinolineacetic acid methylester and 1,950 g of finely ground suppository base composition (forexample cacao butter) are thoroughly mixed and then fused. 1,000suppositories weighing 2,0 g each are cast from the melt, which is kepthomogeneous by stirring. The suppositories each contain 50 mg of activesubstance.

2. 60.0 of polyoxyethylene-sorbitane monostearate, 30.0 g of sorbitanestearate, 150.0 g of paraffin oil and 120.0 g of stearyl alcohol arefused together, 50.0 g of a-methyl-Z-phenyl-o-quinolineacetic acid(finely powdered) are added and 590 ml of water prewarmed to 40 areemulsified in the mixture. The emulsion is stirred until it has cooledto room temperature and is filled into tubes.

The starting materials of the formula II are new and can be obtained ina manner which is in itself known, for example as follows:

An aniline derivative of the formula (V) HZN 1 can be reacted with acompound of the formula ArCH=C(Rg)-C(R2)=O (lVa) by the Doebner- Millermethod in accordance with the reaction conditions described earlier. Itis, however, also possible to condense a compound of the formula 00 CH RH N R with a ketone of the formula Ar-C(=O)CI-l R (IVb) according toFriedlander, under the reaction conditions described earlier. In bothcases starting substances of the formula II, wherein X represents aradical of the formula CH R are obtained.

In compounds of the formula II, wherein X represents a radical of theformula CH R the latter can be halogenated, preferably brominated orchlorinated, in the a-position in a manner which is in itself known,whereby compounds of the formula II are obtained, wherein X represents agroup of the formula -CH(R- )Hal, wherein Hal denotes a halogen,preferably a chlorine or bromine atom. Halogenation is carried out, forexample, with elementary halogen, such as chlorine or bromine, or withhalogen derivatives which can donate halogen radicals, such as withN-halogeno-amides, for example N-bromosuccinimide or N-chlorosuccinimide, or N-bromoacetamide. The reaction is advantageouslyinitiated by the formation of radicals, with radicals being formed byirradiating the reaction mixture with light, advantageously in theultraviolet range, or by the addition of radical-forming agents,advantageously of organic peroxides, such as optionally substitutedbenzoyl peroxides, for example benzoyl peroxide or an optionallysubstituted perbenzoic acid, for example perbenzoic acid or 3-chloroperbenzoic acid. The radical-forming agents are preferablyemployed in catalytic amounts.

The halogenation can be carried out in the absence of a solvent;advantageously, however, an inert solvent is used, for example achlorinated hydrocarbon, such as carbon tetrachloride, chloroform ormethylene chloride, or a lower alkanecarboxylic acid, such as aceticacid. The halogenation is advantageously carried out at normal orelevated temperature, for example between and 120C.

The halogen derivatives thus obtainable can be converted, by treatmentwith hydrocyanic acid or a salt thereof, for example with an alkalimetal cyanide, such as sodium cyanide or potassium cyanide, into thenitriles to be used as starting substances of the formula II. Theintroduction of the nitrile group is advantageously carried out in apolar solvent which is inert under the reaction conditions, for examplein water, a lower alkanol, such as ethanol, or, advantageously, in aliquid amide, such as dimethylformamide or dimethylacetamide, or in asulphoxide, such as dimethylsulphoxide. The reaction is carried out atnormal temperature or at elevated temperature, for example at betweenabout 20 and 120C.

Nitriles of the formula II, wherein R denotes a hydrogen atom can bealkylated in the a-position, in particular by direct alkylation or,advantageously, by indirect alkylation with a reactive ester of a loweralkanol. The direct alkylation is advantageously carried out underconditions which are described earlier in connection with thea'alkylation of compounds of the formula I.

For the indirect alkylation, a nitrile of the formula II, wherein Rrepresents hydrogen, is first reacted with a carbonic acid ester, forexample with a carbonic acid di-lower alkyl ester, such as carbonic aciddiethyl ester, in the presence of a base, and the nitrile acylated inthe a-position is alkylated in accordance with the alkylation processdescribed above, by treatment with a reactive ester of a lower alkanol.The resulting carboxylic acid ester is then saponified, for example bytreatment with aqueous alkali, for example an aqueous alkali metalhydroxide, such as sodium hydroxide, after which the resultingoz-cyanocarboxylic acid compound is decarboxylated to give a nitrilefalling under the formula II. The decarboxylation in most cases alreadytakes place under the saponification conditions but does so reliably onfurther warming, for example in the same solution. The resulting nitriledoes not have to be isolated but can be converted in situ into thecompounds of the present invention.

The imidoesters or thiomidoesters falling under the formula II can beobtained, for example, from the nitriles falling under the formula Ii bythe successive action of a strong acid, preferably a hydrogen halideacid, such as hydrochloric acid, and an alcohol or mercaptan, preferablya lower alkanol. The reaction is advantageously carried out in thepresence of an inert solvent, for example of one of the ether-likesolvents described above, at normal or elevated temperature, say between20 and C.

Compounds of the formula II wherein X denotes a trihalogenomethyl group,preferably a trichloromethyl group, are obtained, for example, if adiazonium salt, manufactured from an amine of the formula II, wherein Xrepresents the amino group, is reacted with a compound of the formula R-CI-I=C(l-Ial) (VII), in which Hal denotes halogen, preferably chlorine,advantageously in the presence of a copper salt, for example a copperhalide, such as copper chloride, in water, or preferably in a mixture ofwater and an inert watermiscible organic solvent, such as a lower alkylketone, for example acetone, a lower alkanonitrile, such asacetonitrile, a lower alkanol, such as ethanol, or one of thewater-soluble ether-like solvents described above, for example dioxane.The reaction is carried out at lowered or elevated temperature, forexample between about 0 and 100C. According to an advantageous form ofcarrying out the process, the diazonium salt is manufactured in theusual manner from the amino compound with sodium nitrite in aqueoushydrochloric acid, the copper salt is added, a solution of the compoundof the formula VII in acetone is gradually added to the solutionobtained, at about 0, and the temperature is slowly raised from 0 to50C.

The compounds of the formula II, wherein X, denotes a tri-loweralkoxymethyl group are obtained, for example, by alcoholysis from thetrihalogenomethyl compounds and alkali lower alkanolates, such as sodiummethylate, preferably in the corresponding lower alkanol as the solvent.

The amines of the formula II, wherein X represents the amino group, areobtained, for example, by reduction of the corresponding nitrocompounds, for example with hydrogen which has been activatedcatalytically, for example with palladium on charcoal. The nitrocommpounds can in turn be manufactured, for example, from correspondingnitroanil compounds in accordance with the methods of synthesis ofquinoline indicated above.

Thiamides falling under the formula II can be manufactured from thecorresponding nitriles by the action of hydrogen sulphide or phosphoruspentasulphide, and also from compounds of the formula II, wherein Xrepresents an acetyl group, by the methods of Willgerodt orWillgerodt-Kindler, by treating with ammonium polysulphide or withammonia or a primary or a secondary amine and sulphur. The reaction withammonium polysulphide is carried out, for example, in a medium whereinone or preferably both reactants are at least partially soluble, forexample dioxane, in a closed vessel at temperatures of around l60220.According to the Kindler modification, the reaction can be carried out,for example, with aqueous or anhydrous ammonia or with a monoor di-loweralkylamine, such as diethylamine, or an alkyleneamine, such aspiperidine, and with sulphur, again in a closed vessel and ifappropriate in the presence of pyridine at temperatures of about C toabout C. According to the customary embodiment of the Kindlermodification, morpholine, of

which the boiling point of 138C renders the use of pressure vesselssuperfluous, is used as the amine. For example, a mixture of a compoundof the formula II, wherein X represents an acetyl group, and of sulphurin excess morpholine is boiled under reflux, whereupon a correspondingthioacetic acid morpholide of the formula II is formed.

The ketones of the formula II, wherein X denotes an acetyl group, whichare used as intermediate products are obtained, for example, byoxidation of a compound of the formula 11, wherein X denotes an ethylgroup. The oxidation can, for example, be effected by treatment withselenium dioxide in the presence of an organic solvent, for example inan ether-like solvent, such as dioxane, at an elevated temperature, forexample at the reflux temperature.

The manufacture of the organo-metallic compounds of the formula II,wherein X represents a group of the formula -CH(R )X (He), in which Xdenotes a metallic radical, these compounds being used as startingsubstances, advantageously starts from halogen compounds of the formulaII, wherein X represents a group of the formula CI-l(R )I-Ial, which arereacted with one of the abovementioned metals, preferably with lithiumor magnesium. It is, however, also possible to react an appropriatehalogen compound with an organo-metallic compound, preferably with alower alkyl-lithium or lower alkyl-magnesium halide, for examplebutyl-lithium, or with an aryl-lithium or arylmagnesium halide, such asphenyl-lithium. The manufacture of the above organo-metallic compounds,which are advantageously not isolated, is preferably carried out in thsolvents described for the further reaction, and at the sametemperatures.

The starting material of the formula II used above, wherein X is a groupof the formula --CH(R )X (lId), wherein X, represents an optionallyetherified hydroxyl group, can be obtained, for example, from a compoundof the formula II, wherein X represents a radical of the formula CI-I(R)-I-Ial, by hydrolysis or alcoholysis, preferably under alkalineconditions, for example by treatment with the abovementioned basicreagents, such as an aqueous-alcoholic solution of an alkali metalhydroxide, such as sodium hydroxide, or with an alkali metal loweralkanolate in a lower alkanol, working, for example at between about and100C.

The manufacture of the above aldehydes of the formula [I used asstarting materials, wherein X represents a group of the formula -CI-I(R)--CI-IO (He), starts, for example, from an organo-metallic compound ofthe formula II, wherein X is the group of the formula Ilc, which isallowed to react with a reactive functional derivative of formic acid,preferably with a formic acid ester, such as one of the abovementionedformic acid lower alkyl esters, or with a suitable substituted 2-oxazolinium salt, such as N,4,4-trimethyl-2- oxazolinium iodide.

The starting substances of the formula II, wherein X represents a groupof the formula Ilg, can be obtained, for example, by condensation of acompound of the formula II, wherein Xrepresents a group of the formulaIlb, in which R denotes hydrogen and X denotes the nitrile group, withan aldehyde or ketone of the formula R =O (VIII). The condensation iscarried out, for example, under the reaction conditions described forthe alkylation of the corresponding nitriles. The resulting oz-loweralkylidene-substituted nitriles can be converted into the correspondingacids, or into their esters or amides, as described above.

The above starting materials of the formula II, wherein X denotes thegroup of the formula IIh or of the formula Ili, can be manufactured, forexample, from the corresponding functional derivatives with regard tothe free carboxyl group, preferably from the esters, especially thelower alkyl esters or benzyl esters, for example by hydrolysis orhydrogenolysis, it also being possible to prepare the acids, used asstarting substances, in situ.

The functional derivatives of the compounds of the formulall, wherein Xdenotes the group of the formula Ilh or Hi, can be manufactured, forexample, by acylation of compounds of the formula II, wherein Xrepresents a radical of the formula III), wherein X, is a nitrile group,with a carbonic acid derivative or an oxalic acid derivative, preferablywith an ester, such as a lower alkyl ester or benzyl ester, for examplewith diethyl carbonate, dibenzyl carbonate, oxalic acid diethyl ester oroxalic acid dibenzyl ester, in the presence of a base, with subsequentsaponification of the nitrile group.

The starting substances of the formula II, wherein X represents a groupof the formula C(=O)-C(N- )-R;,(Ilk), can be obtained by treating acompound of the formula II, wherein X represents a halogenocarbonylgroup, for example a chlorocarbonyl group, with a diazoalkane of theformula R Cl-I=N=N, preferably in the presence of a solvent, for exampleone of the ether-like solvents described above, or a hydrocarbon, at atemperature of about l0 to about 140C.

The acid halides used in the above manufacture of the startingsubstances can be obtained, for example, from the corresponding acids,for example by treatment with a thionyl halide, such as thionylchloride.

Starting materials of the formula III, wherein Z, is hydrogen, are knownor can be manufactured analogously to known compounds.

The starting materials of the formula IlIb can be manufactured in amanner which is in itself known. However, they are advantageouslymanufactured in situ by reaction of an aniline of the formula III,wherein Z, de-

notes hydrogen, with a carboxylic acid, such as formic acid or aceticacid, or a reactive functional derivative thereof, for example with aformic acid lower alkyl ester, such as formic acid ethyl ester, or withacetic anhydride, preferably in the presence of one of the above acidcatalysts. In this reaction variant, for example, an aniline of theformula III is heated with formic acid to a temperature of above thecompound of the formula IV, wherein Z is a group of the formula lVb,such as the acetyl group, and, preferably, a condensation agent, suchas, for example, zinc-chloride, are then added, and the mixture isfurther warmed to about 200 until the condensation is complete.

The examples which follow explain the manufacture of the new compoundsaccording to the invention in more detail but are not intended torestrict the scope of the invention in any way.

EXAMPLE 1 A mixture of 10 g of 2-phenyl-6- quinolineacetonitrile, 19 mlof water, 19 ml of concenare added and the pH is adjusted to 5-6 withsolid so-- dium bicarbonate. The crystals which thereupon precipitateare filtered off and rinsed with water. Recrystallisation frommethanol-ether-petroleum ether yields 2-phenyl-6-quinolineacetic acid ofmelting point 176-179C. 2-( p-Chlorophenyl )-6-quinolineacetic acid and2-(p-fluorophenyl)-6-quinolineacetic acid are obtained analogously.

The 2-phenyl-6-quinolineacetonitrile used as the starting material ismanufactured as follows:

a. A mixture of 400 g of p-toluidine, 171 g of formic acid and 253 g ofzinc chloride is stirred for 4 hours under reflux at a bath temperatureof 150-l 60C. It is cooled to 100C, 224 g of acetophenone are rapidlyadded dropwise and the reaction mixture is stirred for 20 hours at abath temperature of 180190C, whilst distilling off a part of the formicacid through a distillation elbow. Thereafter the reaction mixture iscooled to 100C, 600 ml of a 1:1 mixture of chloroform and ethyl acetateare added and the mixture is boiled under reflux until it can again bestirred easily. The suspension is cooled and the crystals which haveprecipitated are filtered off and thoroughly rinsed with chloroformethylacetate, 1:1, until the filter residue is white. The filtrate isevaporated and the residue is dissolved in ethyl acetate. This solutionis washed three times with concentrated ammonia and then evaporated on arotary evaporator, and the residue is steam-distilled. The residue fromthe steam distillation is extracted with ethyl acetate and the organicphases are then separated off and extracted with 4 times 400 ml of 5 Nhydrochloric acid. The hydrochloric acid extracts are adjusted to pH 8-9and extracted with ethyl acetate. The organic phases are washed withsodium chloride solution, dried over sodium sulphate, combined andconcentrated. Hereupon 2-phenyl-6-methyl-quinoline crystallises out.Melting point 64-65C (from methanol).

Analogously, toluidine and p-fluoroacetophenone yieldZ-(p-fluorophenyl)-6-methyl-quinoline, melting point 106lO7C (fromethanol-water), and toluidine and p-chloroacetophenone yield2-(p-chlorophenyl)-6- methyl-quinoline, melting point l54l55C (fromethanol-ether).

b. A solution of 54 g of Z-phenyl-6-methyl-quinoline, 68 g ofN-bromosuccinimide and 1.5 g of dibenzoyl peroxide in 700 ml of carbontetrachloride is kept for 18 hours under reflux. Thereafter the reactionmixture is cooled to room temperature and the precipitate is filteredoff. The filter residue is rinsed with carbon tetrachloride. Thefiltrate is evaporated and the residue is dissolved in ethyl acetate.This solution is washed with water and sodium chloride solution, driedover sodium sulphate and evaporated. The residue is taken up in 1.8litres of ether and the insoluble constituents are filtered off.Concentration of the solution yields 2-phenyl-6- bromomethyl-quinolineof melting point 126-127C.

Analogously, 2-(p-chlorophenyl)-6-methylquinoline yields2-(p-chlorophenyl)-6-bromomethyl-quinoline of melting point 123-l26C(from carbon tetrachloride) and 2-(p-fluorophenyl)-6-methylquinolineyields 2-(pfluorophenyl)-6-bromomethyl-quinoline of melting point117118C (from carbon tetrachloride).

A solution of 6 g of 2-phenyl-6-bromomethylquinoline and 3 g of sodiumcyanide in 60 ml of dimethylsulphoxide is stirred for 4 hours at 40C.Thereafter 500 ml of ice water are added and the product which hereuponprecipitates is filtered off. When the filter residue is recrystallisedfrom 200 ml of ethanol, Z-pheof melting point EXAMPLE 2 A mixture of 1 1g of a-methyl-2-phenyl-6- quinolineacetonitrile, 23 ml of water, 23 mlof glacial acetic acid and 23 ml of concentrated sulphuric acid isboiled under reflux for 8 hours. The reaction mixture is cooled, treatedwith ice water and adjusted to pH 8 with 2 N sodium carbonate solution.This solution is treated with active charcoal, warmed on a water bathfor 1 hour and then filtered. The filtrate is adjusted to pH 5 withconcentrated hydrochloric acid and the precipitate which hereuponseparates out is filtered off and rinsed with water. Afterrecrystallisation from ethanolwater, a-methyl-Z-phenyl-6-quinolineaceticacid of melting point l6ll62C are obtained.

The following are obtained analogously:

a-Methyl-2-(p-chlorophenyl)-6-quinolineacetic acid of melting point189190C (from ethyl acetatepetroleum ether).

a-Methyl-2-(p-fluorophenyl)-6-quinolineacetic acid of melting point179180C (from ethyl acetatepetroleum ether).

a-Methyl-2-(2-thienyl)-6-quinolineacetic acid melting point l7ll73C(from chloroform).

The a-methyl-2-phenyl-6-quinolineacetonitrile used as the startingmaterial is obtained as follows:

a. 12 g of 2-phenyl-6-quinolineacetonitrile are added at 60C, whilststirring, to a dispersion prepared from 2.6 g of sodium hydridedispersion (50% strength) in 50 ml of toluene. ml of dimethyl carbonateare now added and the mixture is distilled dropwise at a heating bathtemperature of 170C until the boiling point rises to 93C. A further 90ml of dimethyl carbonate are added and the mixture is again distilleduntil the excess dimethyl carbonate has been removed (the boiling pointrises to above 92C). After cooling, the solid residue is treated with 40ml of toluene and 60 ml of the dimethylformamide. Immediately, 9, ml ofmethyl iodide are also added and the reaction mixture is stirred for 18hours at room temperature. Thereafter the reaction mixture is pouredonto 800 ml of ice water and the suspension is well stirred and treatedwtih a little ether. Hereupon, a-cyano-a-methyl-2-phenyl-6-quinolineacetic acid methyl ester, melting at l33l 34C after drying,crystallises out. Further product can be obtained from the aqueous phaseby extraction with ethyl acetate and evaporation of the organicsolution.

The following are obtained analogously:a-cyano-ozmethyl-2-(p-chlorophenyl)-6-quinolineacetic acid methyl ester,a-cyano-a-methyl-Z-(p-fluorophenyl)-6- quinolineacetic acid methyl esterand a-cyano-amethyl-2-(2-thienyl)-6-quinolineacetic acid methyl ester;they are further processed in the crude state.

b. 36.4 ml of 1 N sodium hydroxide solution are added dropwise to asolution of 10.4 g of a-cyano-amethyl-2-phenyl-6-quinolineacetic acidmethyl ester in 580 ml of ethanol at room temperature. The reactionmixture is stirred for 16 hours at room temperature and evaporated todryness, the residue is treated with water and the suspension therebyproduced is filtered off. After drying in vacuo at 40C, crudea-methyl-Z-phenyl-6-quinolineacetonitrile is obtained, which is directlyprocessed further.

The following are obtained analogously: a-methyl-2-(p-chlorophenyl)-6-quinolineacetor1itri1e of melting point 126C (fromethanol), a-methyl-Z-(p-fluorophenyl)-6-quinolineacetonitrile of meltingpoint 126-128C (from ethanol) and crude amethyl-2-(2-thienyl)--quinolineacetonitrile.

EXAMPLE 3 A mixture of 3 g of 2-(2-thienyl)-6- quinolineacetonitrile,8.6 ml of water, 8.6 ml of glacial acetic acid and 8.6 ml ofconcentrated sulphuric acid is boiled for 3 hours under reflux.Thereafter the reaction mixture is cooled, threated with ice water andadjusted to pH 56 with solid sodium bicarbonate. The resultingsuspension is extracted with ethyl acetate and the organic phases arewashed with water, dried over sodium sulphate and evaporated. Theresidue obtained is 2-(2-thienyl)-6-quinolineacetic acid, the meltingpoint of which, after recrystallisation from acetonepetroleum ether, isabout 172C.

The 2-(2-thienyl)-6-quinolineacetonitrile used as the starting materialis obtained as follows:

a. 34 g of zinc chloride are added to a mixture of 53.6 g of p-toluidineand 24 g of formic acid. The mixture is stirred for 3 hours underreflux. Thereafter the reflux condenser is replaced by a distillationelbow, 31.5 g of 2-acetylthiophene are added to the reaction mixture andthe mixture is stirred for 30 hours at a heating bath temperature ofl80200C, in the course of which formic acid distils off. Thereafter themixture is cooled to 100C, a mixture of 100 ml of chloroform and 100 mlof ethyl acetate is added and the whole is stirred for 30 minutes underreflux, whereby a suspension is produced. This is filtered and theresidue is rinsed with ethyl acetatechloroform. The filtrate is washedthree times with concentrated aqueous ammonia solution and with waterand is dried over sodium sulphate and evaporated. The residue ischromatograph graphed on silica gel. 2-(2-Thienyl)-6-methyl-quinoline iseluted with a mixture of petroleum ether and methylene chloride in theratio of 1:1; after recrystallisation from ether/petroleumether/pentane, it melts at 116C.

12. 1 1.9 g of 2-(2-thienyl)-6-methyl-quinoline togehter with 360 ml ofcarbon tetrachloride, 10.4 g of N-bromosuccinimide and 0.3 g ofdibenzoyl peroxide are boiled for hours under reflux. The reactionmixture is cooled and filtered off. Concentration of the filtrate yields2-(2-thienyl)-6-bromomethyl-quinoline which melts at 95C.

0. A solution of 14 g of 2-(2-thienyl)-6- bromomethylquinoline in 150 mlof dimethylsulphoxide is treated with 3.6 g of sodium cyanide. Thereaction mixture is stirred for 40 minutes at 30-40C and subsequentlyfor a further 30 minutes at room temperature. Thereafter it is pouredonto 500 g of ice. After thorough stirring, the product separates out asa precipitate. This is separated off and purified by chromatography onsilica gel. 2-(2-Thienyl)-6- quinolineace tonitrile is eluted withtoluene; after EXAMPLE 4 45 m1 of cinnamaldehyde are added dropwise to amixture of 38 g of p-aminophenylacetic acid, 71g of arsenic acid and 300ml of phosphoric acid. The reaction mixture is stirred for 2 hours at C,50 ml of polyphosphoric acid are then added and the whole is againstirred for 16 hours at 110l20C. The reaction mixture is cooled to 0Cand adjusted to a pH of 5-6 first with 2 N sodium hydroxide solution andthen with solid sodium carbonate. This suspension is extracted withethyl acetate and the organic phases are then extracted 6 times with 50ml of 1 N hydrochloric acid at a time. The hydrochloric extracts arecombined and a few pinches of sodium nitrite are added. The solution isleft to stand for 15 minutes at room temperature and is then adjusted topH 5.6, using a pl-l-meter, by adding sodium carbonate. This solution isextracted with ethyl acetate and the organic layers are washed withwater, dried over sodium sulphate and evaporated. The residue obtainedis crude 2-phenyl-6-quinolineacetic acid. Melting point 176179C (frommethanol-pentane). a-Methyl-Z-phenyl-6-quinolineacetic acid of meltingpoint l61-l62C (from ethanol-water) is obtained analogously.

EXAMPLE 5 A mixture consisting of 1.9 g of a-methyl-Z-(pchlorophenyl-6-quinolineacetic acid, 28 ml of methanol and 28 drops ofconcentrated sulphuric acid is kept for 2 hours under reflux. Thereafterthe reaction mixture is concentrated on a rotary evaporator. The residueis treated with ice, ether and 50 ml of 0.5 N sodium chloride solution.After thorough shaking, the aqueous phase is separated off and theorganic phase is washed with water, dried over sodium sulphate andevaporated. The residue is dissolved in 25 ml of ethyl acetate andtreated with petroleum ether until it crystallises.a-Methyl-Z(p-chlorophenyl)-6-quino1ineacetic acid methyl ester ofmelting point ll4-115C is obtained.

The following are manufactured analogously:a-Methyl-2-(Z-thienyl)-6-quinolineacetic acid methyl ester.a-Methyl-2-phenyl-6-quinolineacetic acid methyl ester of melting point8789C (from ether).

EXAMPLE 6 A mixture of 30 g of p-aminohydratropic acid methyl ester, 7.7g of formic acid and 11.4 g of zinc chloride is stirred under reflux for2 hours at a heating bath temperature of C. Thereafter the refluxcondenser is replaced by a distillation elbow. 20 g of acetophenone areadded to the mixture which is stirred for 16 hours at a heating bathtemperature of 200C, in the course of which a slight amount ofdistillate passes over. The mixture is allowed to cool and the resultingcrude a-methyl-2-phenyl-6-quinolineacetic acid methyl ester ishydrolysed as follows:

A solution of 14 g of potassium hydroxide in 26 ml of water and 260 mlof ethanol is add ed to the reaction mixture and the mixture is stirred,with warming, until a homogeneous suspension has formed. The whiteprecipitate is filtered off and the filtrate is boiled under reflux for3 hours. Thereafter the solution is evaporated to dryness. The residueis distributed between ethyl acetate and water. The aqeuous phase istreated with active charcoal, acidified to pH 6 and extracted with ethylacetate. Drying and evaporation of the ethyl acetate solution yieldscrude a-methyl-2-phenyl-6- quinolineacetic acid. After furtherpurification by chromatography and recrystallisation from ethanolwater,the melting point is 163C.

Analogously, 2-acetylthiophene, p-aminohydratropic acid methyl ester andformic acid yield a-methyl-2-(2-thienyl)-6-quinolineacetic acid ofmelting point l71-173C (from chloroform).

EXAMPLE 7 a-Methyl-2-phenyl-6-quinolineacetic acid (2.77 g) is dissolvedin 10 ml of 1 N sodium hydroxide solution. The solution is evaporated todryness and the residue is dissolved in isopropanol. On cooling thesolution, the sodium salt of a-methyl-2-phenyl-o-quinolineacetic acid,of melting point 275-276C, crystallises out.

EXAMPLE 8 A solution of 1.9 g of 2-phenyl-6-quinolinecarboxylic acid (v.Braun, Ber. 60, 1,255) in 20 ml of methylene chloride is treated with lg of pyridine. 0.7 g of thionyl chloride is then added and the mixtureis boiled for 3 hours under reflux in a nitrogen atomsphere. Aftercooling, the reaction mixture is evaporated to dryness on a rotaryevaporator, absolute benzene is added to the residue which is againevaporated, and this procedure is repeated until the thionyl chloridehas been completely removed. The residue is treated with 20 ml ofabsolute tetrahydrofurane and the suspension thus obtained is addeddropwise over the course of 1 hour at -l0C, whilst stirring, to 70 ml ofan 0.34 molar solution of diazomethane in ether, to which 15 ml ofabsolute dioxane have also been added. The reaction mixture is stirredfor a further hours at room temperature and is then evaporated on arotary evaporator at a bath temperature of 30C.

The residue is dissolved in 36 ml of methanol, the solution is heated tothe refluxing temperature and silver oxide, obtained by reaction of l gof silver nitrate with 1 N sodium hydroxide solution, washing with waterand with methanol, is added in portions until the evolution of gasceases, which requires about 4 hours. Thereafter the precipitate ofsilver is filtered off and the filtrate is evaporated. The2-phenyl-6-quinolineacetic acid methyl ester thereby obtained, togetherwith 1.7 g of potassium hydroxide, 10 ml of ethanol and 1 m1 of water,is kept for 3 hours under reflux and is subsequently left to stand for afurther 10 hours at room temperature. The solution is filtered throughglass wool, which is rinsed with ethanol, and is evaporated. The residueis dissolved in 30 ml of water and this solution is twice washed with 40ml of ether at a time, then warmed on a water bath to remove the ether,and treated with 0.5 g of charcoal. The aqueous solution is now adjustedto a pH of l with concentrated hydrochloric acid and twice washed with50 ml of ether. Thereafter it is adjusted to a pH of 5.6 with solidsodium bicarbonate and extracted with ethyl acetate. Washing, drying andevaporation of the ethyl acetate layers yields 2-phenyl-6-quinolineacetic acid which after recrystallisation frommethanol-ether-petroleum ether melts at 176-l79C.

a-Methyl-2-phenyl-6-quinolineacetic acid of melting point 161-l62C ismanufactured analogously.

EXAMPLE 9 A solution of 2.5 g of crude 2-phenyl-6- quinolineacetaldehydein 3 ml of ethanol is slowly added dropwise at room temperature to asuspension of 3.4 g of silver nitrate and 1.6 g of sodium hydroxide in12 ml of water. After completion of the addition, the mixture is stirredfor a further 3 hours. Thereafter the suspension is clarified byfiltration and the filtrate is washed with ether and adjusted to a pH of6. The emulsion thereby produced is extracted with ethyl acetate. Theethyl acetate extracts, after drying, evaporation and recrystallisationof the residue from methanolpentane, yield 2-phenyl-6-quinolineaceticacid of melting point l76-179C.

Analogously to Example 2-(2-thienyl)-6- quinolineacetaldehyde yields2-(2-thienyl)-6- quinolineacetic acid of melting point 172C.

The 2-phenyl-6-quinolineacetaldehyde used as the starting material isobtained as follows:

a. 6.2 .g of 6-bromomethyl-Z-phenyl-quinoline and magnesium in 30 ml oftetrahydrofurane are used to prepare the corresponding Grignard compoundin the usual manner. 7.9 g of hexamethylphosphoramide are added to thissolution and the mixture is added dropwise at room temperature, whilststirring, to a stirred suspension of 4.8 g ofN,4,4-trimethyl-2-oxazolinium iodide in 60 ml of tetrahydrofurane. Thereaction mixture is stirred for a further 16 hours and is then treatedwith ice water and rendered acid with 2 N hydrochloric acid. The acidsolution is washed with hexane, rendered alkaline with sodium hydroxidesolution and extracted with ether. The ether extracts are evaporated.The residue is treated with a solution of 8 g of oxalic acid in 50 ml ofwater and the mixture is boiled for 15 minutes under reflux. Thesolution is cooled and crude 2-phenyl-6-quinolineacetaldehyde isextracted therefrom with ether; it is used in the crude form.

Analogously, 6-bromomethyl-2-( 2-thienyl)- quinoline yields crude 2-(2-thienyl)-6- quinolineacetaldehyde.

EXAMPLE l0 Dried hydrochloric acid gas is passed into a solution of 25 gof 2-(p-chlorophenyl)-6-quinolineacetonitrile in ml of of absolutemethanol, whilst cooling with ice, until saturation is reached.Thereafter the reaction mixture is left to stand for 16 hours at roomtemperature and evaporated on a rotary evaporator, and the residue istreated with 200 ml of water, 400 ml of dioxane and a little ice. The pHis adjusted to 7 with solid sodium acetate. Thereafter the solution iskept for 10 minutes at 4050C and evaporated, and the residue is treatedwith water. This suspension is twice extracted with 300 ml of ether at atime and the combined ether solutions are washed with l N sodiumcarbonate solution and with saturated sodium chloride solution, driedand concentrated to 40 ml. Thereupon,2-(pchlorophenyl)-6-quinolineacetic acid methyl ester of melting poont ll9l2lC crystallises out.

EXAMPLE 1 l 10 g of Z-(p-chlorophenyl )-a-methyl-6- quinolinemalonicacid are heated to C for 20 minutes. The melt is cooled and dissolved inethyl acetate, and the solution is extracted with 0.5 N sodium carbonatesolution. The sodium carbonate extracts are adjusted to pH 5 andextracted with ethyl acetate. The ethyl acetate extracts, on evaporationand recrystallisation of the residue from ethyl acetatepetroleum ether,-yield 2-(p-chlorphenyl)-a methyI 6-quinolineacetic acid of melting pointl88 -l89."C.

a-Methyl-2-phenyl-6-quinolineacetic acid of melting point 16 l l 62C,2-(p-fluorophenyl)-a-methyl-6- quinolineacetic acid of melting pointl79-180C and a-methyl-2(2-thieny1)-6-quinoline acetic acid of meltingpoint l66-l67C are obtained analogously.

The 2-(p-chlorophenyl)-a-methyl-6- quinolinemalonic acid used as thestarting material is manufactured as follows:

a. 13.9 g of 2-(p-chlorophenyl)-6-quinolineacetic acid methyl ester areadded to a mixture of 2.3 g of sodium hydride dispersion and 90 ml ofdimethyl carbonate. 70 ml of the dimethyl carbonate are now distilledoff, a further 30 ml of dimethyl carbonate are added and this is againdistilled from the reaction mixture. The suspension which remains iscooled to C and 3.2 ml of methyl iodide are added. The mixture isstirred for half an hour at Of'C. a further 3.2 ml of methyl iodide areadded and the mixture is further stirred for 2 hours at 6070C. Thereaction mixture is cooled and poured onto a mixture of 400 ml of icewater and 9 ml of 5 N hydrochloric acid. The suspension thus produced isextracted with ether and the ether phases are washed with saturatedsodium chloride solution, dried, combined and evaporated.2(p-Chlorophenyl)-amethyl-6-quinolinemalonic acid dimethyl ester isobtained as the residue, in the form of a yellowish oil.

b. A mixture of 16.2 g of 2-(p-chlorophenyl)-amethyl-6-quinolinemalonicacid dimethyl ester, 160 ml of butanol, 50 m1 of water and 5.6 g ofpotassium hydroxide is boiled for 4 hours under reflux. Thereafter thereaction mixture is evaporated to dryness, the residue is partitionedbetween ether and water and the aqueous layer is separated off, adjustedto a pH of 5-6 with 5 N hydrochloric acid and extracted with ethylacetate. The ethyl acetate extracts are washed with water until netural,dried and evaporated. The residue obtained is crude2-(p-chlorophenyl)-a-methyl-6- quinolinemalonic acid.

The following crude products are manufactured analogously:a-methyl-2-phenyl-6quinolinemalonic acid,,82(p-fluorophenyl)-a-methyl-6-quinolinemalonic acid, andoz-methyl-2-(2-thienyl)-6-quinolinemalonic acid.

EXAMPLE 12 The Grignard compound is prepared in the customary mannerfrom 5 g of 6-bromomethyl-2-phenylquinoline and magnesium in 30 ml ofdiethyl ether. It is added to a solution of solid carbon dioxide in 100ml of diethyl ether. At the same time a further quantity of solid carbondioxide is added in portions to the reaction solution. Thereafter,aqueous ammonium chloride solution is added to the reaction mixture andthe whole is extracted with ethyl acetate. The organic phases areextracted with 2 N sodium carbonate solution. The sodium carbonateextracts are adjusted to pH 6 and extracted with ethyl acetate. Theseethyl acetate layers are dried and evaporated. The residue, afterrecrystallisation from methanol-pentane, yields 2-phenyl-6-quinolineacetic acid of melting point l76179C.

quinolineacetic acid of melting point 172C.

EXAMPLE 13 A mixture .of 35.8. g of p-aminohydratropic acid methyl esterand 20.5 g of acetic anhydride is treated with 12 g of glacial aceticacid and 13.7 g of zinc chloride. This reaction mixture is stirred'for 3hours at 150C. Thereafter 25.3 g of 2-acetylthiophene are added dropwiseover the course of 10. minutes at C, whilst stirring. The refluxcondenser is replaced by a distillation elbow and the reaction mixtureis stirred for a further 20 hours at 185C. The reaction mixture is nowtreated with chloroform'at C, briefly kept under reflux and thenfiltered. The filter residue is additionally extracted twice withchloroform and is then partitioned between concentrated ammonia solutionand'ethyl acetate. Thechloroform solutions and-the ethyl acetatesolution are combined and evaporated. The residue, crude4a-dimethyl-2-(2-thieny)-6- quinolineacetic acid methyl ester, is keptfor 5 hours under reflux with 22.5 g of potassium hydroxide, 600 ml ofethanol and 33.3 ml of water to produce complete saponification. Thereaction mixture is evaporated. the residueisdissolvedin 700 ml ofwater, and the aqueous solution is washed with ether and combined withthe ammonia solution obtained above. The resulting solution is adjustedto pH 5 and extracted with ethyl acetate. The ethyl acetate solutionsare repeatedly extracted with l N hydrochloric acid. The hydrochloricacid extracts are adjusted to pH 6 and extracted with ethyl acetate andthe organic phases are washed with saturated sodium chloride solution,combined, dried and evaporated. The residue, after recrystallisationfrom methanol, yields 4, a-dimethyl-2-(2-thienyl)- quinolineacetic acidof melting point 228-229C.

What we claim is:

l. A quinolineacetic compound of the formula wherein Ar denotes phenyl,thienyl or phenyl substituted by one or two identical members selectedfrom lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl,amino, di-lower alkylamino, or hydroxy, R represents hydrogen, fluoro,chloro, bromo, lower alkyl, lower alkoxy or trifluoromethyl and R and Rindependently of one another denote hydrogen or lower alkyl, wherein Zis OH, NH OR, NHR, NRR, or NHOH where R is lower alkyl in which lower"defines one to seven carbon atoms, or a pharmaceutically acceptablenon-toxic salt thereof.

2. A compound of the formula I, according to claim 1, in which Ardenotes phenyl, thienyl or phenyl substituted by one or two identicalmembers selected from alkyl or alkoxy with at most four carbon atoms,fluorine, chlorine, bromine or trifluoromethyl, R denotes hydrogen orchlorine, R and R independently of one another denote hydrogen or alkylwith at most four carbon atoms, and wherein one of the groups CH(R)COOl-l and R occupies the 6-position and the other the 8-position andthe group R occupies the 4- position, an alkyl ester with at most fourcarbon atoms, the unsubstituted or N-hydroxy-substituted amide thereof,or a pharmaceutically acceptable non-toxic salt thereof.

3. A compound of the formula 1, according to claim 1, wherein Ar denotesphenyl, thienyl or phenyl substituted by one fluorine, chlorine, methylmethoxy or trifluoromethyl, R denotes hydrogen, R denotes hydrogen ormethyl in the 4-position and R denotes hydrogen or methyl, and whereinthe CH(R COOl-l group occupies the 6-position, a methyl ester or apharmaceutically acceptable non-toxic salt thereof.

4. A compound according to claim 1, which isa-Methyl-2-phenyl-6-quinolineacetic acid methyl ester.

5. A compound according to claim 1, which isa-Methyl-2-(p-chlorophenyl)-6-quinolineacetic acid methyl ester.

6. A compound according to claim 1, which is a-Met- 28hyl-2-(p-fluorophenyl)-6-quinolineacetic acid methyl ester.

7. A compound according to claim 1, which isa-Methyl-2-(2-thienyl)-6-quinolineacetic acid methyl ester.

8. A compound according to claim 1, which is 2-Phenyl--quinolineaceticacid.

9. A compound according to claim 1, which is 2-(p-Chlorophenyl)-6-quinolineacetic acid.

10. A compound according to claim 1, which is2-(pfluorophenyl)-6-quinolineacetic acid.

1 l. A compound according to claim 1, which is 2-(2- thienyl)-6-quinolineacetic acid.

12. A compound according to claim 1, which isa-methyl-2-phenyl-6-quinolineacetic acid.

13. A compound according to claim 1, which isa-methyl-2-(p-chl0rophenyl)-6-quinolineacetic acid.

14. A compound according to claim 1, which isa-methyl-2-(p-fluorophenyl)-6-quinolineacetic acid.

15. A compound according to claim 1, which isa-methyl-2-(Z-thienyl)-6-quinolineacetic acid.

16. A compound according to claim 1, which is 401-dimethyl-2-(2-thienyl)-6-quinolineacetic acid.

1. A QUINOLINEACETIC COMPOUND OF THE FORMULA
 2. A compound of theformula I, according to claim 1, in which Ar denotes phenyl, thienyl orphenyl substituted by one or two identical members selected from alkylor alkoxy with at most four carbon atoms, fluorine, chlorine, bromine ortrifluoromethyl, R1 denotes hydrogen or chlorine, R2 and R3independently of one another denote hydrogen or alkyl with at most fourcarbon atoms, and wherein one of the groups -CH(R3)COOH and R1 occupiesthe 6-position and the other the 8-position and the group R2 occupiesthe 4-position, an alkyl ester with at most four carbon atoms, theunsubstituted or N-hydroxy-substituted amide thereof, or apharmaceutically acceptable non-toxic salt thereof.
 3. A compound of theformula I, according to claim 1, wherein Ar denotes phenyl, thienyl orphenyl substituted by one fluorine, chlorine, methyl methoxy ortrifluoromethyl, R1 denotes hydrogen, R2 denotes hydrogen or methyl inthe 4-position and R3 denotes hydrogen or methyl, and wherein the-CH(R3) COOH group occupies the 6-position, a methyl ester or apharmaceutically acceptable non-toxic salt thereof.
 4. A compoundaccording to claim 1, which is Alpha -Methyl-2-phenyl-6-quinolineaceticacid methyl ester.
 5. A compound according to claim 1, which is Alpha-Methyl-2-(p-chlorophenyl)-6-quinolineacetic acid methyl ester.
 6. Acompound according to claim 1, which is Alpha-Methyl-2-(p-fluorophenyl)-6-quinolineacetic acid methyl ester.
 7. Acompound according to claim 1, which is Alpha-Methyl-2-(2-thienyl)-6-quinolineacetic acid methyl ester.
 8. A compoundaccording to claim 1, which is 2-Phenyl-6-quinolineacetic acid.
 9. Acompound according to claim 1, which is2-(p-Chlorophenyl)-6-quinolineacetic acid.
 10. A compound according toclaim 1, which is 2-(p-fluorophenyl)-6-quinolineacetic acid.
 11. Acompound according to claim 1, which is 2-(2-thienyl)-6-quinolineaceticacid.
 12. A compound according to claim 1, which is Alpha-methyl-2-phenyl-6-quinolineacetic acid.
 13. A compound according toclaim 1, which is Alpha -methyl-2-(p-chlorophenyl)-6-quinolineaceticacid.
 14. A compound according to claim 1, which is Alpha-methyl-2-(p-fluorophenyl)-6-quinolineacetic acid.
 15. A compoundaccording to claim 1, which is Alpha-methyl-2-(2-thienyl)-6-quinolineacetic acid.
 16. A compound accordingto claim 1, which is 4 Alpha -dimethyl-2-(2-thienyl)-6-quinolineaceticacid.